Sleep apnea (ICD-10: G47.3) is generally defined as an intermittent reduction or stop of airflow at the nose and mouth during sleep. Sleep apnea spans over a wide range of upper airway flow changes resulting in arousal of the patient (brief awakening from sleep), alteration of tissue blood gas and pH, as well as endocrine, paracrine, hemodynamic and vascular changes. In its simplest form sleep apnea may be characterized by subtle airflow restriction typically associated with sleep fragmentation that results in daytime sleepiness or various degrees of cognitive dysfunction.
Sleep apnea associated with daytime symptoms, specifically daytime hypersomnolence (sleepiness), is generally referred to as the Obstructive Sleep Apnea Syndrome (OSAS). Beside hypersomnolence, cognitive and mood changes provide a substantial burden on general health in patients with this condition. Hypersomnolence has been associated with complications including reduced working and driving performance, with an increased risk for accidents.
Moreover, cardiovascular complications, in particular hypertension, cardiac failure, cardiac arrhythmia, myocardial infarction and stroke have been strongly associated with sleep apnea.
Sleep apnea has furthermore been associated with increased insulin resistance, diabetes, obesity, changes in lipid metabolism, increased inflammation and platelet aggregation.
The prevalence of sleep apnea in the adult population depends on clinical laboratory cutoff values applied for the condition. Epidemiological studies suggest that sleep apnea defined as an apnea-hypopnea index (AHI) (number of apneas per hour of sleep) equal to or higher than 5 occurs in 24% of working adult men and in 9% of adult women.
The detailed pathophysiology of sleep apnea is unknown but is likely to include multiple mechanisms such as, but not limited to, dysfunctional chemical control of respiration, insufficient muscular control of the airway or structural anatomical obstruction of the airway during sleep, frequently caused by obesity or tonsillar hypertrophy.
In conclusion, sleep apnea is a significant clinical problem. Sleep apnea results in a considerably reduction of quality of life and a considerable risk of high blood pressure, myocardial infarction and stroke for a substantial part of the patients with this condition.
Despite intense research in the field there is no efficient pharmacological treatment for sleep apnea today.
The principal forms of treating or preventing sleep apnea includes surgery of the upper airway and use of medical devices (various forms of positive airway pressure (PAP) devices), intra-oral mandibular advancement devices, positional therapy and nerve stimulation devices.
Surgery is not uniformly effective. In particular, surgery is frequently associated with relapse of symptoms.
PAP treatment involves wearing a face mask that covers the airways during sleeping. Patients frequently find this therapy uncomfortable. Although often effective, this method has poor long-term compliance.
An intra-oral mandibular advancement device is a device that is worn in the mouth and which moves the lower jaw forward during sleep. These devises are frequently uncomfortable and low long-term compliance is moderate. Also, they are not always effective.
Positional therapy (trying to make patients to sleep on the side rather than on the back) may be partly effective in some patients. Long term compliance is low.
Hypoglossal and phrenic nerve stimulation are under development and is not always effective. Long term compliance is not fully characterized.
Various forms of pharmacological treatment, e.g., tricyclic antidepressants, theophylline, progesterone, zonisamide (Eskandari D et al, (2014) Eur Respir J: 44:140-149) and topiramate (together with another compound) (Winslow D et al, (2012) Sleep 35:11 1529-1539) have been tried. Zonisamide and topiramate both have carbonic anhydrase inhibitory activity as part of their activity profiles. However, these compounds have not gained any wide clinical use as efficacy has been limited and since side effects have been prominent. Both zonisamide and topiramate have cognitive side effects which due to their seriousness limit the use of these compounds in patients with sleep apnea. In addition, the use of topiramate has been associated with an increased risk of suicide. Zonisamide and topiramate are mainly used for the treatment of epilepsy, where these side effects have been considered acceptable from a risk-benefit perspective.
US20160045527 and WO 2011085256 each propose the use of carbonic anhydrase inhibitors such as topiramate or zonisamide in combination by co-administration with other compounds such as aldosterone antagonists or a non-benzodiazepine sedative agent for the treatment of sleep apnea. However, those patent applications are speculative as no experimental evidence is provided for efficacy or side effects.
Carbonic anhydrase catalyses the interconversion of CO2 and water to bicarbonate and protons. There are at least sixteen carbonic anhydrase isoenzymes, and they all have different activity profiles. Several inhibitors of carbonic anhydrases are known. It has been acknowledged that that the inhibition profiles for the various carbonic anhydrase isoenzymes may explain the difference in efficacy in various clinical applications for the carbonic anhydrase inhibitors. (Supuran C., (2008) Nature Reviews Drug Discovery, February 2008, 168-181). Supuran further states that the various carbonic anhydrase inhibitors have been extensively studied and exploited for several diseases.
Acetazolamide, which is a prototype inhibitor of carbonic anhydrase, has been reported to be useful for the treatment of sleep apnea (Tojima H. et al, (1988) Thorax; 43:113-119). Acetazolamide is one of the most commonly used carbonic anhydrase inhibitors, and is the carbonic anhydrase inhibitor reported to most effectively reduce sleep apnea. Drawbacks of acetazolamide treatment include frequent occurrence of paraesthesia (a sensation of tingling, tickling, pricking, or burning) and these side effects limit a wide use of acetazolamide in the clinical setting. The use of acetazolamide for the treatment of sleep apnea has therefore not gained a wide acceptance.
In general, the current treatments for sleep apnea are associated with a number of drawbacks, and there is a need for novel treatments of sleep apnea. In particular there is a need for an improved pharmacological treatment of sleep apnea that brings improved efficacy and tolerable side effects, in particular lower frequency of paraesthesia.
It has now surprisingly been found that sultiame shows higher efficacy than acetazolamide in the treatment of sleep apnea. Sultiame has a high efficacy in sleep apnea and has a surprisingly favourable side effect profile. Sultiame (Sulthiam; Sultiam; Ospolot; Contravul; Sulphenyltame) (4-(1,1-dioxothiazinan-2-yl benzenesulfonamide) is a carbonic anhydrase inhibitor drug known since the 1950s. Today the use of sultiame is limited. Sultiame is mainly used for certain rare forms of childhood epilepsy (benign Rolando epilepsy, BECTS), in German-speaking countries.